Targeting Topics 07q2

Cholinergic modulation of sensory interference in rat primary somatosensory cortical neurons

Alenda A, Nunez A

Brain Res 1133(1):158-167, 2007.

One critical feature of cognition is the ability to focus on selected sensory inputs while ignoring irrelevant inputs. In this work the authors examine basal forebrain participation in sensory interference effects. Following 0.15 µg bilateral injections of 192-IgG-SAP (Cat. #IT-01) into the basal forebrain of rats, the ability of primary somatosensory cortical neurons to respond in the presence of sensory interference was assessed. A decrease in the number of neurons showed sensory interference in lesioned animals.

Substance P-saporin down-regulates substance P receptor immunoreactive sensory dorsal root ganglion neurons innervating the lumbar intervertebral discs in rats

Ohtori S, Inoue G, Koshi T, Ito T, Doya H, Moriya H, Takahashi K

Spine 31(26):2987-2991, 2006.

Neurokinin-1 (NK-1) receptor expressing neurons that innervate lumbar intervertebral discs may be involved in lower back pain. Here the authors investigate the basic effect of SP-SAP (Cat. #IT-07) on neurons innervating the L5/6 intervertebral disc. Rats were injected with 175 ng of SP-SAP. The number of NK-1 receptor expressing neurons was reduced by over 75% in the treated animals, demonstrating SP-SAP as a useful tool to investigate the mechanism of discogenic low back pain, particulary for investigating behavioral impacts.

Selective lesions of the nucleus basalis magnocellularis impair cognitive flexibility

Cabrera SM, Chavez CM, Corley SR, Kitto MR, Butt AE

Behav Neurosci 120(2):298-306, 2006.

In humans, one aspect of cognitive flexibility is being able to shift attention under a variety of pressures. Here the authors suggest that lesions to the cholinergic nucleus basalis magnocellularis (NBM) will impair cognitive flexibility. The NBM of rats was lesioned with 0.08 µg of 192-IgG-SAP (Cat. #IT-01). Both lesioned and controlled animals displayed a similar ability to learn a discrimination task, but lesioned animals displayed perseveration – the uncontrollable repetition of a previously correct response – indicating a loss of cognitive flexibility.

Extensive training in a maze task reduces neurogenesis in the adult rat dentate gyrus probably as a result of stress

Aztiria E, Capodieci G, Arancio L, Leanza G

Neurosci Lett 416(2):133-137, 2007.

Ascending cholinergic inputs from the basal forebrain modulate hippocampal neurogenesis, although it is not clear if the modulation is direct or indirect. In this study rats experienced extended training in a spatial navigation task following 192-IgG-SAP (Cat. #IT-01) lesions. 192-IgG-SAP was injected into the basal forebrain nuclei and the cerebellar cortex. Although the lesioned animals displayed an 80% reduction in neuron proliferation in the dentate gyrus, extended training and learning did not affect proliferation.

Guanidinylated-Neomycin delivers large, bioactive cargo into cells through a heparan sulfate dependent pathway

Elson-Schwab L, Garner OB, Schuksz M, Esko JD, Tor Y

J Biol Chem 282(18):13585-13591, 2007.

The uptake of high molecular weight drugs into cells is a stumbling block for some potential therapeutics. Using a neomycin derivative in which guanidinium groups have replaced the ammonium groups, the authors show heparan sulfate-dependent uptake of large molecules. The guanidine-neomycin was biotinylated, and incubated with streptavidin-ZAP (Cat #IT-27). This complex was effective in killing CHO cells in vitro, but was no more effective than streptavidin-ZAP alone on cells lacking heparan sulfate expression, demonstrating specificity.

Targeted deletion of neurokinin-1 receptor expressing nucleus tractus solitarii neurons precludes somatosensory depression of arterial baroreceptor-heart rate reflex

Potts JT, Fong AY, Anguelov PI, Lee S, McGovern D, Grias I

Neuroscience 145(3):1168-1181, 2007.

Previous work by these authors examined the role of substance P in arterial baroreflex. Here, 1.5 ng bilateral injections of SP-SAP (Cat. #IT-07) into the caudal nucleus tractus solitarii of rats were used to further elucidate the fundamental role of substance P in this system. The depressive effect of somatosensory input by neurokinin-1 receptor-expressing neurons on arterial baroreceptor-heart rate reflex was abolished in lesioned animals. (See Cover Story.)

Selective cholinergic depletion of the hippocampus spares both behaviorally induced Arc transcription and spatial learning and memory

Fletcher BR, Baxter MG, Guzowski JF, Shapiro ML, Rapp PR

Hippocampus 17 (3):227-234, 2007.

The immediate early gene Arc is required for long-term synaptic changes and memory consolidation. The authors lesioned the fornix to examine cholinergic contributions of the medial septum and the vertical diagonal band to spatial learning impairments and behavioral induction of Arc transcription. 0.24-0.36 µg of 192-IgG-SAP (Cat. #IT-01) was delivered to the fornix of rats. Results from various water-maze tasks indicate that spatial learning deficits and impaired Arc transcription associated with lesions of the fornix are not caused by cholinergic deafferentation.

From anxiety to autism: spectrum of abnormal social behaviors modeled by progressive disruption of inhibitory neuronal function in the basolateral amygdala in Wistar rats

Truitt WA, Sajdyk TJ, Dietrich AD, Oberlin B, McDougle CJ, Shekhar A

Psychopharm (Berl) 191(1):107-118, 2007.

The amygdala has been identified as being involved in social behaviors. Six 4 ng injections of SSP-SAP (Cat. #IT-11) were administered bilaterally into the basolateral nucleus (BLA) of the amygdala of rats. Blank-SAP (Cat. #IT-21) was used as a control. Results of a social interaction paradigm suggest that in normal animals social inhibition can be overcome by habituation. In lesioned animals, however, social inhibition is not reversed by habituation, indicating that NK-1 receptor-expressing GABAergic interneurons in the BLA are important in this system.

Astrocytic reaction to a lesion, under hormonal deprivation

Martinez L, de Lacalle S

Neurosci Lett 415(2):190-193, 2007.

One effect of estradiol on astrocytes is the mediation of neuronal sprouting. Astrocytes express glial fibrillary acidic protein (GFAP) in response to injury, but estradiol has been shown to repress GFAP expression. Ovariectomized female rats received 15 ng of 192-IgG-SAP (Cat. #IT-01) into the horizontal limb of the diagonal band of Broca, followed by long-term estrogen treatment. The results suggest that estradiol deprivation may exacerbate the effects of a cholinergic lesion, and administration of estradiol may aid the recovery of lesioned cholinergic neurons by blocking GFAP expression.

Targeted Delivery and Enhanced Cytotoxicity of Cetuximab-Saporin by Photochemical Internalization in EGFR-Positive Cancer Cells

Yip WL, Weyergang A, Berg K, Tonnesen HH, Selbo PK

Mol Pharm 4(2):241-251, 2007.

Photochemical internalization (PCI) releases macromolecules from endocytic vesicles using photosensitizer activation by light. This technique allows the release of endocytosed molecules before degradation occurs in the lysosome. The authors demonstrate the proof-of-concept for this technique by combining biotinylated cetuximab (a chimeric monoclonal antibody to the EGFr) with streptavidin-ZAP (Cat. #IT-27). The conjugate was applied to three different human cancer cell lines, demonstrating enhanced specificity and toxicity against cells expressing the EGFr.

Lesions to the nucleus basalis magnocellularis lower performance but do not block the retention of a previously acquired learning set

Bailey AM, Lee JM

Brain Res 1136(1):110-121, 2007.

A major source of cholinergic innervation to several cortices is the nucleus basalis magnocellularis (NBM). Rats were trained to acquire an olfactory discrimination learning set, then were lesioned with 192-IgG-SAP (Cat. #IT-01) or quisqualic acid. 0.075 µg of 192-IgG-SAP was administered in 2 sets of bilateral infusions. While treated animals performed poorly following the surgery, performance improved to better than expected by chance during the second trial. The authors discuss the role of the NBM in cognitive flexibility.

Noncholinergic lesions of the medial septum impair sequential learning of different spatial locations

Dwyer TA, Servatius RJ, Pang KC

J Neurosci 27(2):299-303, 2007.

The medial septum and the vertical limb of the diagonal band of Broca (MSDB) have extensive connections to the hippocampus. In general, impairments due to loss of cholinergic neurons in this area have been smaller than those due to the loss of noncholinergic neurons. The authors treated rats with either 192-IgG-SAP (Cat. #IT-01) or kainic acid into each hemisphere of the medial septum. Behavioral testing following surgery demonstrated that the animals with noncholinergic lesions had impaired performance, even when compared to the animals with cholinergic lesions.

Extracellular signal-regulated kinase-regulated microglia-neuron signaling by prostaglandin E2 contributes to pain after spinal cord injury

Zhao P, Waxman SG, Hains BC

J Neurosci 27(9):2357-2368, 2007.

Spinal cord injury frequently leads to the development of long-term chronic pain. Recent data has shown that activated microglia are involved in the maintenance of this pain state. Following a spinal cord contusion injury rats were treated with a 36-µg injection of Mac-1-SAP (Cat. #IT-06) into the lumbar enlargement. Treated animals were found to have reduced microglial staining, reduction in prostaglandin E2 levels, and fewer pain-related behaviors.

Decreased vesicular acetylcholine transporter and alpha(4)beta(2) nicotinic receptor density in the rat brain following 192 IgG-saporin immunolesioning

Quinlivan M, Chalon S, Vergote J, Henderson J, Katsifis A, Kassiou M, Guilloteau D

Neurosci Lett 415(2):97-101, 2007.

The vesicular acetylcholine transporter (VAChT) is a useful imaging target to assess Alzheimer’s disease, since this transporter is expressed on cholinergic cells that are lost as the disease progresses. Through the use of 192-IgG-SAP (Cat. #IT-01) the authors demonstrate the use of two radioligands, one that binds VAChTs, the other which binds nicotinic acetylcholine receptors (nAChRs). The results show the efficacy of each radioligand, as well as the loss of nAChRs on cholinergic neurons after treatment with 192-IgG-SAP.